EP2613810B9 - Biologisch abbaubare wasserlösliche und ph-reaktive poly(organo)phosphazene - Google Patents

Biologisch abbaubare wasserlösliche und ph-reaktive poly(organo)phosphazene Download PDF

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EP2613810B9
EP2613810B9 EP10752318.5A EP10752318A EP2613810B9 EP 2613810 B9 EP2613810 B9 EP 2613810B9 EP 10752318 A EP10752318 A EP 10752318A EP 2613810 B9 EP2613810 B9 EP 2613810B9
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poly
organo
oxide
glycol
molecule conjugate
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EP2613810A1 (de
EP2613810B1 (de
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Ian P. Teasdale
Sandra Wilfert
Ivo Nischang
Oliver BRÜGGEMANN
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JOHANNES KEPLER UNIVERSITAET LINZ
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JOHANNES KEPLER UNIVERSITAT LINZ
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A61K47/551—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/605—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the macromolecule containing phosphorus in the main chain, e.g. poly-phosphazene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates in general to the field of targeted drug delivery of anti-cancer drugs. More precisely, the present invention concerns polymer drug conjugates, namely, conjugates of poly(organo)phosphazenes and anti-cancer drugs, wherein the conjugates are suitable to selectively release anti-cancer drugs in tumor tissue.
  • the present invention relates to a method for manufacturing such poly(organo)phosphazene molecule conjugates, to poly(organo)phosphazene molecule conjugates for use in medicine, in particular, to poly(organo)phosphazene molecule conjugates for use in the treatment of cancer, and to pharmaceutical compositions comprising such poly(organo)phosphazene molecule conjugates.
  • Anti-cancer drugs used to control the growth of cancerous cells are commonly known to have severe side effects, since healthy tissue is always affected by these drugs.
  • anthracycline antibiotics such as epirubicin, doxorubicin, daunorubicin, idarubicin and valrubicin, are a group of highly effective DNA intercalators derived from Streptomyces bacteria.
  • Anthracycline antibiotics as some of the most effective anti-cancer drugs are used to treat a wide range of cancers, including leukemias, lymphomas, breast, uterine, ovarian, and lung cancers.
  • anthracycline antibiotics also exhibit severe side effects due to their high toxicity towards healthy tissue.
  • One of the main side effects of anthracycline antibiotics are cardiotoxicity, which considerably limits their usefulness, and vomiting.
  • taxanes and vinca alkaloids are anti-cancer drugs interfering with microtubule and mitotic spindle, respectively, and therefore, always affect both tumor and healthy tissue.
  • anti-cancer drugs are usually highly hydrophobic and, therefore, exhibit poor aqueous solubility. Thus, administration via blood stream is always critical. In addition, most anti-cancer drugs are rapidly eliminated from the body and therefore, have to be administered repeatedly in order to ensure constant therapeutic levels.
  • EPR enhanced permeability and retention
  • tumor vasculature is, in principle, more permeable than healthy tissue
  • the haphazard structure of tumor tissue due to the fast growth of the cells and its poor lymphatic system means removal is slow, particularly for larger macromolecules, and therefore, leads to accumulation of these molecules.
  • accumulation is observed to increase with increasing molecular weight (Maeda, H. et al., 2000).
  • choice and design of the macromolecule is of particular significance for its potential as drug delivery system of anti-cancer drugs.
  • Poly(organo)phosphazenes are a class of macromoleculare polymers of inorganic/organic hybrid type. Due to their synthetic flexibility, hydrolytic degradability and non-toxic degradation products, poly(organo)phosphazenes have been reported to have tremendous potential as materials for biomedical applications (EI-Amin, S.F. et al., 2006).
  • the polymer backbone of such poly(organo)phosphazenes consists of alternating phosphorus and nitrogen atoms (scheme 1), wherein organic substituents are linked to the phosphorus atoms as side chain groups.
  • US 6,319,984 concerns biodegradable and thermosensitive poly(organo)phosphazenzes having depsipeptide and amino acid ethylester side groups for use as drug delivery system in general. More specific poly(organo)phosphazenes are disclosed in US 2009/0181088 teaching poly(organo)phosphazene-bioactive molecule conjugates. These conjugates containing various bioactive molecules are biodegradable and thermosensitive poly(organo)phosphazenes with a functional group showing sol-gel phase transition upon temperature alteration.
  • poly(organo)phosphazenes of US 2009/0181088 forms (after administration to the human body) a gel-phase at body temperature and, therefore, allows controlled release of the bioactive molecules.
  • gel-phase forming properties at body temperature means that these poly(organo)phosphazenes are not suitable to be administered into the blood stream.
  • treatment of cancer would be much more effective and less toxic, if a drug delivery system could be provided suitable to selectively deliver and, additionally, to selectively release anti-cancer drugs in tumor tissue.
  • the object of the present invention in one preferred embodiment thereof, is solved by a poly(organo)phosphazene molecule conjugate wherein the anti-cancer drug is covalently linked to the polymer backbone via a pH-sensitive linker.
  • the present invention relates to a poly(organo)phosphazene molecule conjugate represented by formula 1: wherein,
  • the poly(organo)phosphanzes molecule conjugates of the present invention are suitable to selectively release anti-cancer drugs in tumor tissue.
  • the extracellular pH of tumor tissue has a pH of about 4-6 and is, therefore, significantly lower than the extracellular pH of healthy tissue, which is approximately around 7.4. Since the poly(organo)phosphazene molecule conjugates of the present invention covalently link anti-cancer drugs via the pH sensitive functional group "Y", the anti-cancer drug of the conjugate will be only released in an acidic (tumor) environment.
  • covalently linking of anti-cancer drugs via a pH sensitive functional group to poly(organo)phosphazenes allows the drug to be selectively released when the polymer-drug conjugate is transported and accumulated in tumor tissue.
  • Drugs can also be loaded onto macromolecular carriers via non-covalent interactions (for example hydrophobic or hydrogen-bonding interactions).
  • non-covalent interactions for example hydrophobic or hydrogen-bonding interactions.
  • a major problem of this method is that the drug molecules can leak out prematurely from the macromolecular carrier before it has reached the site of action. Some may leak out prior to the site of action and affect healthy tissue (Lee, MacKay et al. 2005)
  • the polymer Being able to covalently bind the drug to the polymer according to the present invention is therefore of significant advantage.
  • the polymer must also be able to release its load rapidly when it reaches the site of action. If the drug molecule is directly bound to the polymer then biodegradation of the polymer is required before the drug is released ( US Patent 20091811088 ).
  • employing a polymer that degrades more slowly will lead to a slower release of the drug and delayed therapeutic action and a reduced efficacy, if polymer degradation is relied upon as the drug release mechanism.
  • an acid-sensitive linkage ensures - for the first time utilising poly(organo)phosphazenes - rapid release of the drug exclusively in the required environment, i.e. tumor tissue.
  • a "pH-sensitive functional group" means any functional group which will respond to a pH lower than 6.5, i.e. which will be hydrolysed by a pH of lower than 6.5.
  • the pH-sensitive functional group of the present invention will respond to a pH lower than 6.5, 6.4, 6.3, 6.4, 6.3, 6.2, 6.1, 6.0, 5.9, 5.8, 5.7, 5.6, 5.5, 5.4, 5.3, 5.2, 5.1, 5.0, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1 and 4.0.
  • the pH-sensitive functional group of the present invention will respond to a pH in the range of 4.0 to 6.5, preferably, in the range of 4.5 to 6.0, more preferably, in the range of 4.5 to 6.0, and most preferably, in the range of 5.0 to 6.0 .
  • any functional group cleavable in an acidable environment pH lower than 6.5, preferably lower than 6.0
  • the pH sensitive functional group is selected from the group consisting of hydrazide, hydroxamate, imine, cyclic acetal and aconityl.
  • the pH sensitive group "Y" within formula 1 is represented by one formula 2 to 7 selected from the group consisting of
  • a pH sensitive linker is reacted with the polymeric backbone selected from the group consisting of formula 8 to 13: wherein X and R1 are defined as above.
  • R 1 is selected from the group consisting of (C 1 to C 9 )-alkyl, (C 1 to C 9 )-alkenyl, (C 1 to C 9 )-alkinyl, (C 1 to C 9 )-alkoxy, (C 1 to C 9 )-alkenoxy, (C 1 to C 9 )-acyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, arylalkenyl, (C 1 to C 9 )-heteroalkyl, (C 1 to C 10 )-heteroalkenyl, (C 1 to C 9 )-heteroalkinyl, (C 1 to C 9 )-heteroalkoxy, (C 1 to C 9 )-heteroalkenoxy, (C 1 to C 9 )-heteroacyl, heterocycloalkyl, heterocycloalkyl, heterocyclo
  • R 1 is selected from the group consisting of (C 1 to C 8 )-alkyl, (C 1 to C 8 )-alkenyl, (C 1 to C 8 )-alkinyl, (C 1 to C 8 )-alkoxy, (C 1 to C 8 )-alkenoxy, (C 1 to C 8 )-acyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, arylalkenyl, (C 1 to C 8 )-heteroalkyl, (C 1 to C 8 )-heteroalkenyl, (C 1 to C 8 )-heteroalkinyl, (C 1 to C 8 )-heteroalkoxy, (C 1 to C 9 )-heteroalkenoxy, (C 1 to C 8 )-heteroacyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarykalkenyl, heteroarylalky
  • R 1 is selected from the group consisting of (C 1 to C 7 )-alkyl, (C 1 to C 7 )-alkenyl, (C 1 to C 7 )-alkinyl, (C 1 to C 7 )-alkoxy, (C 1 to C 7 )-alkenoxy, (C 1 to C 7 )-acyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, arylal-kenyl, (C 1 to C 7 )-heteroalkyl, (C 1 to C 7 )-heteroalkenyl, (C 1 to C 7 )-heteroalkinyl, (C 1 to C 7 )-heteroalkoxy, (C 1 to C 7 )-heteroalkenoxy, (C 1 to C 7 )-heteroacyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarykalkenyl, heteroarylal
  • alkyl is understood as saturated, linear or branched hydrocarbons, which can occur unsubstituted, mono- or polysubstituted.
  • (C 1 to C 7 )-alkyl represents C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl
  • (C 1 to C 8 )-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8-alkyl
  • C 1 to C 9 )-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-,C8 or C9-alkyl
  • (C 1 to C 10 )-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or C10-alkyl.
  • Alkyls of the present invention are, for example, methyl, ethyl, propyl, isopropyl, methylethyl, butyl, tert-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-methylpentyl, if substituted also CHF 2 , CF 3 or CH 2 OH etc.
  • substituted is understood as meaning replacement of at least one hydrogen radical by F, Cl, Br, I, NH 2 , SH or OH.
  • monosubstituted means the replacement of one hydrogen radical by F, Cl, Br, I, NH 2 , SH or OH, wherein "polysubstituted” (more than once substituted) is means that the replacement takes effect both on different and on the same atoms several times, e.g.
  • alkenyl as used herein is understood as unsaturated, linear or branched hydrocarbons containing at least one double bond, which can be unsubstituted, mono- or polysubstituted.
  • (C 1 to C 7 )-alkenyl represents C1-, C2-, C3-, C4-, C5-, C6- or C7-alkenyl
  • (C 1 to C 8 )-alkenyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8-alkenyl
  • C 1 to C 9 )-alkenyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-,C8 or C9-alkenyl
  • (C 1 to C 10 )-alkenyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or
  • Alkenyls of the present invention are, for example, methenyl, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, tert-butenyl, pentenyl, hexenyl, octenyl, butadienyl, and allenyl groups.
  • alkinyl as used herein is understood as unsaturated, linear or branched hydro-carbons containing at least one triple bond, which can be unsubstituted, mono- or polysub-stituted.
  • (C 1 to C 7 )-alkinyl represents C1-, C2-, C3-, C4-, C5-, C6- or C7-alkinyl
  • (C 1 to C 8 )-alkinyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8-alkinyl
  • C 1 to C 9 )-alkinyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-,C8 or C9-alkinyl
  • (C 1 to C 10 )-alkinyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9
  • Alkinyls of the present invention are, for example, methinyl, ethinyl, propinyl, isopropinyl, butinyl, isobutinyl, tert-butinyl, pentinyl, hexinyl, octinyl, and allinyl groups.
  • alkoxy and alkenoxy refers to an alkyl and alkenyl, respectively, as defined above, which is linked to oxygen and which can be unsubstituted, mono-or polysubstituted.
  • (C 1 to C 7 )- alkoxy represents C1-, C2-, C3-, C4-, C5-, C6-or C7- alkoxy
  • (C 1 to C 8 )- alkoxy represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8- alkoxy
  • C 1 to C 9 )- alkoxy represents C1-, C2-, C3-, C4-, C5-, C6-, C7-,C8 or C9- alkoxy
  • (C 1 to C 10 )- alkoxy represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or
  • (C 1 to C 7 )- alkenoxy represents C1-, C2-, C3-, C4-, C5-, C6- or C7- alkenoxy
  • (C 1 to C 8 )-alkenoxy represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8- alkenoxy
  • (C 1 to C 9 )- alkenoxy represents C1-, C2-, C3-, C4-, C5-, C6-, C7-,C8 or C9- alkenoxy
  • (C 1 to C 10 )- alkenoxy represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or C10- alkenoxy.
  • alkoxy and alkenoxy of the present invention are methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, octoxy,groups, methenoxy, ethenoxy, propenoxy, butenoxy, pentenoxy, hexenoxy, octenoxy groups, etc.
  • R is an alkyl, alkenyl, alkinyl, cycloalkyl or cycloalkenyl as defined herein which can be unsubstituted, mono- or polysubstituted.
  • (C 1 to C 7 )- acyl represents C1-, C2-, C3-, C4-, C5-, C6- or C7- acyl
  • (C 1 to C 8 )- acyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8- acyl
  • (C 1 to C 9 )- acyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-,C8 or C9- acyl
  • (C 1 to C 10 )- acyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or C10- acyl.
  • Examples of "acyl” are methanoyl-, acetoyl-, ethanoyl-, propanoyl-, butanoyl-, malonyl-, benzoyl-
  • cycloalkyl or "cycloalkenyl” as used herein is a subdefinition of “alkyl” or “alkenyl” as defined above and is a carbon ring which can be unsubstituted, mono- or polysubstituted.
  • cycloalkyl or “cycloalkenyl” typically refers to C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 or C 10 cycloalkyl or cycloalkenyl, preferably refers to C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl or cycloalkenyl and may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cyclooctenyl groups.
  • a “heteroalkyl”, “heteroalkenyl”, “heteroalkinyl”, “heteroyalkoxy”, “heteroalkenoxy”, “heteroacyl”, “heterocycloalkyl”, “heterocycloalkenyl”, “heteroaryl”, “heteroarylalkenyl”, or a “heteroarylalkyls” are defined as an alkyl, an alkenyls an alkinyl, an alkoxy, an alkenoxy, an acyl, a cycloalkyl, a cycloalkenyl, an aryl, an arylalkenyl or an arylalkyl, as defined above, wherein said structures contain 0-7 heteroatoms selected from O, N or S, which replace at least one carbon atom in the alkyl, an alkenyls an alkinyl, an alkoxy, an alkenoxy, an acyl, a cycloalkyl or
  • aryl or “heteroaryl” as used herein refers to a 5- or 6-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N or S, a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system ring containing 0-5 heteroatoms selected from O, N or S, or a tricyclic 13- or 14 membered aromatic or heteroaromatic ring system containing 0-7 heteroatoms selected from O, N or S and which can be unsubstituted, mono- or polysubstituted.
  • the aromatic 6- to 14-membered ring systems include e.g.
  • phenyl, naphthalene, indane, tetraline, and fluorene and the 5- to 10-membered aromatic heterocycloc ringsystems include e.g. imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furane, benzimidazole, chinolin, isochinoline, chinoxaline, pyrimidine, pyrazine, tetrazole, pyrazole, pyrrole, imidazole, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothi
  • Arylalkyl, arylalkenyls, heteroarylalkyl, heteroalkylalkenyl, heterocycloalkyl, heterocycloalkenyl moieties are each defined as their corresponding basic structures alkyl, alkenyl, aryl, heteroaryl, heteroalkyl, or heterocycloalkyl.
  • any of the above alkyl, alkenyl, alkinyl, alkoxy, alkenoxy, acyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, arylalkenyls, heteroalkyl, heteroalkenyl, heteroalkinyl, heteroalkenyl, heteroalkoxy, heteroalkenoxy, heteroacyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl groups may either be unsubstituted or (mono- or poly-) substituted with one or more non-interfering substituents, e.g., halogen, alkoxy, acyloxy, hydroxy, mercapto, carboxy, benzyloxy, phenyl, benzyl, or other functionality which may or has been suitably blocked with a protecting group so as to render the functionality non-interfering.
  • Each substituent may be optionally substituted with additional non-interfering substitu
  • Anti-cancer drugs also commonly known as “cytostatics”
  • cytostatics are any drug known in the art suitable to treat cancer, i.e. to treat malignancies, or cancerous growths in order to control the growth of cancerous cells.
  • the anti-cancer drug of the present invention is selected from the group consisting of antibiotics, si-RNA, antisense RNA, alkylating agents, platinum analogues, intercalating drugs, antibiotics, mitotic inhibitors, taxanes, topoisomerase inhibitors, anti-metabolites, hydroxycarbamid, podophyllotoxin, enzymes, hormones, tumor necrosis factor, biological response modifiers and any other known cytostatic.
  • the anti-cancer drug of the poly(organo)phophazene molecule conjugate according to the present invention is selected from the group consisting of aminolevulinic acic, abarelix, abiraterone, aclacinomycins, agatolimoc, alitretinoin, altretamine, americium, amifostine, aminoglutethimice, aminopterin, amrubicin, amsacrine, anastrozole, ancitabine, adjine, aprinocarsen, arsenic trioxice, arzoxifene, asparaginase, atrasentan, axitinib, azaciticine, batimastat, belinostat, belotecan, bencamustine, bevacizumab, bexarotene, bicalutamice, biricocar, bisantrene, bleomycins, bortezomibm bosutinib
  • the anti-cancer drug of the poly(organo)phophazene molecule conjugate according to the present invention is selected from the group consisting of epirubicin, doxorubicin, daunorubicin, idarubicin and valrubicin.
  • the anti-cancer drug is epirubicin.
  • the release of epirubicin from the polymer-drug conjugates was simulated under physiological conditions at 37°C in a pH 7.4 phosphate buffer and in an acidic medium at pH 5 in an acetate buffer solution.
  • pH 5 a steady release of the drug molecule from the polymer was observed, with 100% release from the polymer-drug conjugate being observed within 15 hours. Meanwhile, only minimal release was observed within a period of 24h from the polymers at pH 7.4 ( Figure 2 ).
  • polyalkylene oxide is a polymer composed of repeating oxyalkylene units (-OR-), for example CH 2 O, C 2 H 6 O, C 3 H 6 O, C 4 H 8 O, or combinations thereof, from 2 to 800 repeat units, preferably 10-50 repeat units. They can be linear or branched, but must be overall hydrophilic. Preferred polymers comprise majority (>50%) -C 2 H 6 O- units. The polymers should be end-capped with a non-nucleophilic group at one end, preferably CH 3 O or C 2 H 7 O and a nucleophilic moeity at the other end, preferably NH 2 .
  • Poly(organo)phosphazenes comprising polyalkylene oxides exhibit enhanced water solubility, hydrodynamic volume and number of arms to the polymers.
  • an increased number of arms of the macromolecular carrier decrease renal filtration and therefore, exhibit increased blood circulation time (Fox, M. E., et al., 2009).
  • R 3 and/or R 4 and/or R 5 and/or R 6 and/or R 7 represents a polyalkylene oxide as defined above.
  • the polyalkylene oxide is selected from the group consisting of polyether, methoxypolyether, ethoxypolyether, polyethylene oxide, polypropylene oxide, polybutylene oxide, polyethylene glycol, polypropylene glycol, polybutylene glycol, methoxypolyethylene oxide, methoxypolypropylene oxide, methoxypolybutylene oxide, methoxypolyethylene glycol, methoxypolypropylene glycol, methoxypolybutylene glycol, ethoxypolyethylene oxide, ethoxypolypropylene oxide, ethoxypolybutylene oxide, ethoxypolyethylene glycol, ethoxypolypropylene glycol, ethoxypolybutylene glycol, poly(ethylene oxide-co-propylene oxide), poly(ethylene glycol-co-propylene glycol), poly(ethylene oxide-co-butylene oxide), poly(ethylene oxide-co-butylene oxide), poly(ethylene oxide-co-butylene oxide), poly
  • Depsipetide means a peptide, wherein one or more peptide linkages are substituted by ester linkages, i.e. a peptide in which one or more of the amide (-CONHR-) bonds are replaced by ester (COOR) bonds.
  • depsipeptide is selected from the group consisting of beauvericin, morpholinedione, valinomycin, Depsipeptide A, Depsipeptide B, ethyl-2-(O-glycyl)glycolate and ethyl-2-(O-glycyl)lactate.
  • amino acid alkyl ester is an alkyl derivative of an amino acid, i.e. an ester formed by an amino acid and an alkanol, wherein the alkanol is an alkyl, as defined above, carrying an OH-moiety, preferably an (C 1 to C 10 )-alkyl.
  • an amino acid is any natural or non-natural amino acid selected from the group consisting of Alanine, Arginine, Asparagine, Aspartic Acid, Cysteine, Glutamic Acid, Glutamine, Glycine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Proline, Serine, Threonine, Tryptophan, Tyrosine, Valine, 2-Aminoadipic acid, 3-Aminoadipic acid, beta-Alanine, beta-Aminopropionic acid, 2-Aminobutyric acid, 4-Aminobutyric acid, piperidinic acid, 6-Aminocaproic acid, 2-Aminoheptanoic acid, 2-Aminoisobutyric acid, 3-Aminoisobutyric acid, 2-Aminopimelic acid, 2,4 Diaminobutyric acid, Desmosine, 2,2'-Diaminopimelic acid, 2,3-Diaminopropionic acid,
  • polyphosphazenes have been shown to degrade to low toxicity compounds including ammonia and phosphates (Allock, H. R. et al., 1994).
  • hydrophilic amino substituted polyphosphazenes are known to be hydrolytically unstable and the stability can be tailored by careful choice of substituents such as depsipeptides or amino acid esters.
  • R 3 and/or R 4 and/or R 5 and/or R 6 and/or R 7 represents a depsipeptide as defined above.
  • R 3 and/or R 4 and/or R 5 and/or R 6 and/or R 7 represents an amino acid alkyl ester as defined above.
  • a “tumor targeting ligand” means any substance specifically targeting tumor-specific antigens and/or tumor-specific receptors.
  • the folate receptor has been shown to be over-expressed in many human cancers (Lu, Y. and Low, P.S., 2002).
  • folic acid binding to the folate receptor is a "tumor targeting ligand”.
  • R 3 and/or R 4 and/or R 5 and/or R 6 and/or R 7 represents an amino acid alkyl ester as defined above.
  • Poly(organo)phosphazene molecule conjugates of the present invention comprising at least one tumor targeting ligand have the advantage to selectively target tumor tissue.
  • the tumor targeting ligand is selected from the group consisting of biotin, folic acid, vitamin B12, riboflavin, hyaluronic acid, monoclonal antibodies targeting tumor-specific antigens and/or tumor-specific receptors and variants thereof, polyunsaturated fatty acids, aptamers targeting tumor-specific antigens and/or tumor-specific receptors, oligopeptides targeting tumor-specific antigens and/or tumor-specific receptors.
  • tumor-specific antigen or receptor means any antigen and/or receptor which specifically is expressed within tumor tissue.
  • the sum of a, m, n and l is ⁇ 150, preferably the sum of a, m, n and l is ⁇ 140, ⁇ 130, ⁇ 120, ⁇ 110, ⁇ 100, ⁇ 90, ⁇ 80.
  • the sum of a, m, n and l is in the range of 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 90, 1 to 80, and 1 to 75, alternatively, the sum of a, m, n and l is in the range of 5 to 150, 5 to 140, 5 to 130, 5 to 120, 5 to 110, 5 to 100, 5 to 90, 5 to 80, and 5 to 75, alternatively, the sum of a, m, n and l is in the range of 10 to 150, 10 to 140, 10 to 130, 10 to 120, 10 to 110, 10 to 100, 10 to 90, 10 to 80, and 10 to 75, alternatively, the sum of a, m, n and l is in the range of 15 to 150, 15 to 140, 15 to 130, 15 to 120, 15 to 110, 15 to 100, 15 to 90, 15 to 80, and 15 to 75, alternatively, the sum of a, m, n and I is in the range of
  • a represents a degree of polymerisation of the poly(organo)phosphazenes in the range of 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 90, 1 to 80, and 1 to 75
  • "a” represents a degree of polymerisation of the poly(organo)phosphazenes in the range of 5 to 150, 5 to 140, 5 to 130, 5 to 120, 5 to 110, 5 to 100, 5 to 90, 5 to 80, and 5 to 75
  • "a” represents a degree of polymerisation of the poly(organo)phosphazenes in the range of 10 to 150, 10 to 140, 10 to 130, 10 to 120, 10 to 110, 10 to 100, 10 to 90, 10 to 80, and 10 to 75
  • "a” represents a degree of polymerisation of the poly(organo)phosphazenes in the range of 10 to 150, 10 to 140, 10 to 130, 10 to 120, 10 to 110, 10 to 100, 10 to 90, 10
  • m represents an integer between 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 90, 1 to 80, and 1 to 75
  • “m” represents an integer between 5 to 150, 5 to 140, 5 to 130, 5 to 120, 5 to 110, 5 to 100, 5 to 90, 5 to 80, and 5 to 75
  • “m” represents an integer between 10 to 150, 10 to 140, 10 to 130, 10 to 120, 10 to 110, 10 to 100, 10 to 90, 10 to 80, and 10 to 75
  • “m” represents an integer between 15 to 150, 15 to 140, 15 to 130, 15 to 120, 15 to 110, 15 to 100, 15 to 90, 15 to 80, and 15 to 75
  • “m” represents an integer between 20 to 150, 20 to 140, 20 to 130, 20 to 120, 20 to 110, 20 to 100, 20 to 90, 20 to 80, and 20 to
  • n and “l” are the same or different and each of n and l is independently from one another an integer between 1 and 149, preferably, between 1 to 139, 1 to 129, 1 to 119, 1 to 109, 1 to 99, 1 to 89, 1 to 79, and 1 to 74, alternatively, "n” and “l” are the same or different and each of n and l is independently from one another an integer between 1 to 145, 1 to 140, 1 to 135, 1 to 130, 1 to 125, 1 to 120, 1 to 115, 1 to 110, 1 to 105, 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 75, and 1 to 70, alternatively, "n” and “l” are the same or different and each of n and l is independently from one another an integer between 5 to 145, 5 to 140, 5 to 135, 5 to 130, 5 to 125, 5 to 120,
  • X is NH
  • R 3 and/or R 4 and/or R 5 and/or R 6 and/or R 7 represents R 1 -Y-R 2 , wherein R 1 -Y-R 2 is defined as above.
  • the molecular architecture and hydrodynamic volume of the polymer plays a crucial role in the pharmacokinetics and in-vivo distribution of polymeric drug carriers (Fox, M. E., et al., 2009), accurate control of both molecular weight and dispersity is an important factor for polymer therapeutics.
  • the polydispersity index is the weight average molecular weight divided by the number average molecular weight and, therefore, a measure of the distribution of molecular mass in a given polymer sample.
  • the PDI indicates the distribution of individual molecular masses in a batch of polymers.
  • a PDI equal to or little above 1 indicates that the distinct polymer chains in a given polymer sample approach uniform chain length, i.e. only one length of polymer is present.
  • a PDI around 10 to 20 refers to a batch of polymers having polymer chains varying in chain lengths over a wide range of molecular masses.
  • the poly(organo)phosphazene has a polydispersity of 1.8 or less, preferably, the poly(organo)phosphazene has a polydispersity of 1.7 or less, more preferably of 1.6 or less, even more preferably of 1.5 or less and most preferably of 1.4 or less.
  • dichloropolyphosphazene the major precursor of poly(organo)phosphazenes is dichloropolyphosphazene.
  • Dichloropolyphosphazene is extremely hydrolytically unstable, however, can be readily substituted to give a wide range of stable poly(organo)phosphazenes with an extremely wide range of properties.
  • dichloropolyphosphazenes synthesized by thermal ring-opening polymerisation generally have high molecular weights (M w >10 6 daltons) and, in addition, broad polydispersities, i.e. polydispersity indexes (PDI) up to 19.
  • the present invention concerns a process for preparing a poly(organo)phosphazenes conjugates according to the present invention, comprising cationic living polymerisation of chlorophosphoranimines.
  • the present invention relates to a process for preparing a poly(organo)phosphazene molecule conjugate according to the present invention, comprising the steps of:
  • “Living cationic polymerisation” is known in the art.
  • dichloropolyphosphazenes are synthesised by the polymerisation of chlorophosphoranimine utilising living polymerisation according to Allock, H.R., 1996 and US Patent 5698664 .
  • This simple room temperature polymerisation results in polymers with narrow polydispersities, i.e. polydispersities of 1.8 or less.
  • the polymerised dichloropolyphosphazene of step a) of the process of the present invention has a polydispersity of 1.8 or less, preferably, of 1.7 or less, more preferably, of 1.6 or less, even more preferably of 1.5 or less and most preferably of 1.4 or less.
  • the polymerised dichloropolyphosphazene of step a) of the process of the present invention has a polydispersity in the range of 1.0 to 1.8, preferably, 1.1 to 1.7, more preferably, in the range of 1.2 to 1.6 and most preferably, in the range of 1.3 to 1.5.
  • the polymers in this state are very hydrolytically unstable, due to the labile chlorine groups and must be stored in a dry, inert atmosphere. It is also critical that all reagents used in the polymerisation and subsequent reactions are extremely dry as H 2 O reacts readily with dichloropolyphosphazenes.
  • labile chlorine atoms are that they can then be readily substituted with the desired nucleophilic substituents, such as alcohols, thiols or amines.
  • nucleophilic substituents such as alcohols, thiols or amines.
  • amine-capped organic reagents in THF wherein any dry polar solvent, such as dioxane would be also suitable
  • triethylamine as a scavenger for the HCl by-product
  • the pH sensitive linker can be any linker resulting in a "pH sensitive functional group" as defined above, i.e a "pH-sensitive functional group” which will respond to a pH lower than 6.5, i.e. which will be hydrolysed by a pH of lower than 6.5.
  • the pH-sensitive functional group of the present invention will respond to a pH lower than 6.5, 6.4, 6.3, 6.4, 6.3, 6.2, 6.1, 6.0, 5.9, 5.8, 5.7, 5.6, 5.5, 5.4, 5.3, 5.2, 5.1, 5.0, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1 and 4.0.
  • the pH-sensitive functional group of the present invention will respond to a pH in the range of 4.0 to 6.5, preferably, in the range of 4.5 to 6.0, more preferably, in the range of 4.5 to 6.0, and most preferably, in the range of 5 to 6.0 .
  • any functional group cleavable in an acidable environment pH lower than 6.5, preferably lower than 6.0
  • the pH sensitive functional group is selected from the group consisting of hydrazide, hydroxamate, imine, cyclic acetal and aconityl.
  • the pH sensitive linker is selected from the group consisting of formula 8 to 13 wherein X and R1 are defined as above.
  • the pH sensitive linker is selected from the group consisting of formula 14 to 19
  • the pH sensitive linker is protected before step b).
  • protected refers to a group that is added to an oxygen or nitrogen atom to prevent its further reaction during the course of derivatization of other moieties in the molecule in which the oxygen or nitrogen is located.
  • oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.
  • the protecting group is selected from the group consisting of allyloxycarbonyl (Aloc), benzyl (Bn), benzyloxycarbonyl (Cbz), benzyloxymethyl (BOM), tert-butoxycarbonyl (Boc), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), p-methoxybenzyl (PMB), methoxymethyl (MOM), p-methoxyphenyl (PMP), tosyl (Ts), 2-tosylethoxycarbonyl (Tsoc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), triisopropylsilyl (TIPS), trityl (Tr), fluorenylmethyl carbamate, fmoc, t-butyl carbamate, benzyl carbamate, acetamide, tosylamide, tripheny
  • the protected pH sensitive linkers are selected from the group consisting of formula 20 to 25: wherein PG is a protecting group as defined above.
  • the protected pH sensitive linkers are selected from the group consisting of formula 26 to 31
  • a hydrazone-containing linker capped with an ethylamine group and a boc protecting group could be used for the present invention.
  • Such linker has a free amine group, for reaction with the polymer backbone.
  • the boc-protected hydrazide linker could be then added to the dichloropolyphosphazene.
  • the process for preparing poly(organo)phosphazenes of the present invention further comprises the step of substitution of at least one chlorine atom with a polyalkylene oxide between steps b) and c).
  • the process for preparing poly(organo)phosphazenes of the present invention further comprises the step of substitution of at least one chlorine atom with a depsipeptide between steps b) and c).
  • the process for preparing poly(organo)phosphazenes of the present invention further comprises the step of substitution of at least one chlorine atom with an amino acid alkyl ester between steps b) and c).
  • the process for preparing poly(organo)phosphazenes of the present invention further comprises the step of substitution of at least one chlorine atom with a tumor targeting ligand between steps b) and c).
  • a tumor targeting ligand any tumor-targeting ligand known in the art and suitable to be covalently bound to polyalkylene oxide oligomers could be used.
  • polyethylene glycol oligomers were synthesised with an additional folic acid tumor-targeting ligand in a separate reaction, wherein the diamino polyethylene glycol oligomers were firstly protected on one end. The remaining amino group was then allowed to react with folic acid via a well-reported coupling procedure with EDCI.
  • step d) was performed by replacing the remaining chlorine atoms with mono amine-capped polyalkylene oxide oligomers.
  • mono amine-capped polyalkylene oxide oligomers add water solubility, hydrodynamic volume and number of arms to the polymers (in this respect it should be noted that a large number of arms might also be an important factor for renal clearance).
  • amine-capped Jeffamines ® are used for this purpose. The excess PEO-PPO-NH 2 and remaining salts are then removed by dialysis.
  • the present invention relates to the polyorganophosphazene molecule conjugates obtainable by the process according to the present invention.
  • the present invention relates to the polyorganophosphazene molecule conjugates according to the present invention or to the polyorganophosphazene molecule conjugates obtainable by the process according to the present invention for use in medicine, preferably for use in the treatment of cancer.
  • the present invention relates to pharmaceutical compositions comprising a polyorganophosphazene molecule conjungate according to present invention or a polyorganophosphazene molecule conjugate obtainable by the process according to the present invention and a pharmaceutically active carrier.
  • compositions as defined herein typically can be formulated by methods known to those skilled in the art preferably utilizing pharmaceutically acceptable components.
  • pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding factors such as formulation, stability, patient acceptance and bioavailability.
  • a pharmaceutically acceptable carrier and/or vehicle typically includes the liquid or non-liquid basis of the inventive pharmaceutical composition.
  • the carrier will be typically pyrogen-free water; isotonic saline or buffered (aqueous) solutions, e.g. phosphate, citrate etc. buffered solutions.
  • the injection buffer may be hypertonic, isotonic or hypotonic with reference to the specific reference medium, i.e. the buffer may have a higher, identical or lower salt content with reference to the specific reference medium, wherein preferably such concentrations of the afore mentioned salts may be used, which do not lead to damage of cells due to osmosis or other concentration effects.
  • Reference media are e.g. liquids occurring in "in vivo" methods, such as blood, lymph, cytosolic liquids, or other body liquids, or e.g. liquids, which may be used as reference media in "in vitrd' methods, such as common buffers or liquids.
  • common buffers or liquids are known to a skilled person. Ringer-Lactate solution is particularly preferred as a liquid basis.
  • the present invention concerns compounds for use in a method of treatment of cancer which are poly(organo) phosphazenes according to the present claims.
  • the poly(organo) phosphazene according to the present invention is to be administered into the blood stream, i.e. intravenously.
  • PCl 5 was purified by sublimation and stored under argon. Triethylamine was dried over molecular sieves and distilled prior to use. All other chemicals were purchased from Sigma Aldrich and used without prior purification. All glassware was dried in an oven overnight prior to use.
  • FTIR spectra were measured with a Perkin Elmer Spectrum 100 FTIR spectrometer.
  • a 1290 Infinity UPLC system (Agilent Technologies, Vienna, Austria) equipped with a diode array detector and a Zorbax Eclipse Plus C18 column (2.1 mm x 50 mm, 1.8 ⁇ m particle size) was used for kinetic studies of the drug release.
  • the samples were eluted at a flow rate of 0.5 mL/min at room temperature with a mobile phase composition of 25 % acetonitrile in water (v/v) containing 0.1 % formic acid (v/v) in isocratic mode. UV detection was carried out at 254 nm in the linear range of the detector.
  • ⁇ -Ala-OH (5.00 g, 22.4 mmol)
  • boc-NH-NH 2 (2.96g, 22.4 mmol)
  • EDCI N -(3-dimethylaminopropyl)- N ethylcarbodiimide hydrochloride
  • Polymers were synthesised according to Allcocks' procedure for the living cationic polymerisation of chlorophosphoranimine (Allock, H.R. et al., 1996). The following example procedure describes the procedure used for the synthesis of polymer 1. Other polymers were synthesised accordingly, with the ratio of monomer to initiator varied and the relative amounts of substituents adjusted in order to obtain polymers desired polymers.
  • initiator PCl 5 (18.55 mg, 0.09 mmol) and monomer Cl 3 PNTMS (0.51 g, 2.26 mmol) were dissolved in CH 2 Cl 2 (5 mL) at room temperature. The solution was stirred for 12h and the solvent removed under vacuum. The resulting polydichlorophosphazene was then dissolved in anhydrous THF in an inert atmosphere. 0.2 equivalent of the hydrazide linker (0.18 g, 0.91 mmol) and NEt 3 (0.09 g, 0.91 mmol) were then added to the polymer solution and allowed to react for 24 hours.
  • the release of the anticancer drug from the hydrazone-linked poly(phosphazene) epirubicin conjugates was carried out at 37°C in aqueous buffers in the dark.
  • An incubator was used to control the temperature of the sample solutions during the release experiments.
  • the polymer-drug conjugates were incubated in aqueous buffer solutions at pH 5 (0.1 M sodium acetate) and pH 7.2 (0.1 M phosphate), respectively.
  • the sample vials were only removed from the incubator for the short time of the analysis with UPLC (ultra performance liquid chromatography).
  • a 1290 Infinity UPLC system (Agilent Technologies, Vienna, Austria) equipped with a diode array detector and a Zorbax Eclipse Plus C18 column (2.1 mm x 50 mm, 1.8 ⁇ m particle size) was used for kinetic studies of the drug release.
  • the samples were eluted at a flow rate of 0.5 ml/min at room temperature with a mobile phase composition of 25 % acetonitrile in water (v/v) containing 0.1 % formic acid (v/v) in isocratic mode. UV detection was carried out at 254 nm in the linear range of the detector.
  • Injections of 1 ⁇ l were performed in regular time intervals after addition of the buffer solution to the PPZ-EPI conjugates (2.5 mg/ml) and the amount of EPI released from the PPZ was determined.
  • the calibration was carried out with the pure substance epirubicin hydrochloride in acetate buffer (0.1 M, pH 5) in a concentration range from 1 ⁇ g/ml to 50 ⁇ g/ml.
  • the linear response of the detector was confirmed by a correlation coefficient >0.99.
  • the peak areas allowed calculation of the concentration of free EPI in the sample solutions.
  • Polymer samples (0.20g) were dissolved in a pH 7.4 phosphate buffer (5 mL) and incubated at 37°C. An aliquot (0.25 mL) was then removed at regular intervals and the solvent was evaporated. The polymer was then dissolved in THF, filtered through a 45 ⁇ m PTFE filter and analysed by GPC with an RI detector.
  • Dichloropolyphosphazenes were synthesised by the polymerisation of chlorophosphoranimine according to scheme 2. This simple room temperature polymerisation results in hydrolytically unstable polymers with narrow polydispersities. The chlorine atoms were then substitued with the required amount of boc-protected hydrazide linker (scheme 11).
  • Polymers 5 and 6 were also synthesized with an additional folic acid tumor-targeting ligand.
  • the folate receptor has been shown to be over-expressed in many human cancers (Lu, Y.J. et al., 2002) and its conjugation to macromolecular, carriers has been successfully implemented by a number of authors (Lu, Y.J. et al., 2002, Zhang, Y.Q. et al., 2010; Pan, D. et al., 2003, Zhang, Y.H. et al., 2010).
  • FA-PEO-NH 2 (M n ⁇ 1940) was synthesised via coupling of the ⁇ - carboxylic acid group to a mono boc-protected diamine.
  • the boc protected hydrazide groups on the polymers were deprotected with CF 3 COOH and the resulting amine groups allowed to react with carbonyl group in the side chain of the anti-cancer drug epirubicin (a stereoisomer doxorubicin) (scheme 12).
  • polymers all showed good water solubility but the incorporation of a third different side chain led to a small increase in the polydispersity. As shown in figure 3 , the degradation is considerably accelerated upon incorporation of ethyl glycinate side groups. After 2 weeks, the Mn of polymer 7, in which around 47% of the chlorine atoms were substituted with ethyl glycinate groups, was reduced to 66% of its original value, whereby polymer 2 had an Mn value 80% of its original.
  • the present invention describes the synthesis of hydrophilic, biodegradable polyphosphazenes via the living polymerisation procedure.
  • the polymers can be readily decorated with a combination of targeting ligands and drug molecules.
  • the present invention demonstrates the pH triggered release of an anti-cancer drug from the polymer drug conjugates, as well as the tailoring of the biodegradability by incorporation of amino acid ester side groups.
  • the polymers represent of the present invention extremely promising candidates for the targeted delivery of anti-cancer drugs.
  • the cisplatin pro-drug of formula 32 is formed by a simple reaction of the well known compound Pt (IV)Cl 2 (OH) 2 (NH 3 ) 2 with an anhydride (Aryal, Hu et al.).
  • the platinum IV pro-drug would be rapidly reduced to upon release to platinum II and hence would release the actual free drug cisplatin and not the conjugate.
  • a second example involves the synthesis of a prodrug of Paclitaxel LEV-PTX as reported in the literature (Alani, Bae et al.).
  • LEV-PTX (formula 34, centre) would allow the simple coupling of this common anti-cancer drug to our polyphosphazene system via the carbonyl group at positon 4.
  • An imine linker can be realised by reaction of the readily available n-boc ethylenediamine with chloropholyphosphazene in an analgous reaction to that described for the hydrazide linker above. Following deprotection, the amine bond can react with a carbonyl functionality of a given drug compound. The imine bond hydrolyses much slower than the hydrazide bond and is therefore less preferable.
  • a hydroxamate linker can be easily synthesised using standard synthetic procedures. Readily available benzyl protected alanine can be reacted with the chloropolyphosphazene using the general procedure reported in the patent. The polymer would then be completely substituted with polyalkylene oxide chains as reported in the patent. Following simple deprotection and activation with an N-hydroxysuccinimide group (NHS) using standard synthetic procedures, the polymer is reacted with N-methylhydroxylamine hydrochloride or hydroxylamine as per (Kenawy, EI-Newehy et al. 2007), to give the hydroxamate linker. This linker can bind to any carboxylate group of a given anti-cancer drug.
  • NHS N-hydroxysuccinimide group
  • Aconitic anhydride reacts with n-boc ethylenediamine (Yoo, Lee et al. 2002). This product can then be used for the substitution of chloropolyphosphazene.
  • the carboxylic acid group can be used to couple anti-cancer drugs via an amine group.

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Claims (17)

  1. Poly(organo)phosphazenmolekülkonjugat, dargestellt in Formel 1,
    Figure imgb0040
     wobei
    a einen Polymerisationsgrad der Poly(organo)phosphazene im Bereich von 1 bis 150 darstellt;
    m eine ganze Zahl zwischen 1 bis 150 ist;
    n und I gleich oder unterschiedlich sind und n und I jeweils unabhängig voneinander eine ganze Zahl zwischen 0 bis 149 ist;
    X O, S oder NH darstellt;
    Y eine pH-sensitive funktionale Gruppe darstellt, wobei die pH-sensitive funktionale Gruppe ausgewählt ist aus der Gruppe bestehend aus Hydrazid, Hydroxamat, Imin, zyklisches Acetal und Aconityl;
    R1 ausgewählt ist aus der Gruppe bestehend aus (C1 bis C10)-Alkyl, (C1 bis C10)-Alkenyl, (C1 bis C10)-Alkinyl, (C1 bis C10)-Alkoxy, (C1 bis C10)-Alkenoxy, (C1 bis C10)-Acyl, Zykloalkyl, Zykloalkenyl, Aryl, Arylalkyl, Arylalkenyl, (C1 bis C10)-Heteroalkyl, (C1 bis C10)-Heteroalkenyl, (C1 bis C10)-Heteroalkinyl, (C1 bis C10)-Heteroalkoxy, (C1 bis C10)-Heteroalkenoxy, (C1 bis C10)-Heteroacyl, Heterozykloalkyl, Heterozykloalkenyl, Heteroaryl, Heteroarylalkenyl, Heteroarylalkyl und Polyalkylenoxid;
    R2 ein Antikrebsmittel darstellt;
    R3, R4, R5, R6 und R7 gleich oder unterschiedlich sind und R3, R4, R5, R6 und R7 jeweils unabhängig voneinander ausgewählt sind aus der Gruppe bestehend aus R1-Y-R2, Polyalkylenoxid, Depsipeptid, Aminosäurealkylester und einem auf einen Tumor gerichteten Liganden.
  2. Das Poly(organo)phosphazenmolekülkonjugat nach Anspruch 1, wobei die pH-sensitive Gruppe "Y" in Formel I dargestellt ist durch eine Formel ausgewählt aus der Gruppe bestehend aus den Formeln 2 bis 7:
    Figure imgb0041
    Figure imgb0042
  3. Das Poly(organo)phosphazenmolekülkonjugat nach Anspruch 1 oder 2, wobei die Summe von a, m, n und I ≤ 150 ist.
  4. Das Poly(organo)phosphazenmolekülkonjugat nach einem der Ansprüche 1 bis 3, wobei n und I gleich oder unterschiedlich sind und n und I jeweils unabhängig voneinander eine ganze Zahl zwischen 1 bis 149 ist.
  5. Das Poly(organo)phosphazenmolekülkonjugat nach einem der Ansprüche 1 bis 4, wobei X NH ist.
  6. Das Poly(organo)phosphazenmolekülkonjugat nach einem der Ansprüche 1 bis 5, wobei das Antikrebsmittel ausgewählt ist aus der Gruppe bestehend aus Antibiotika, si-RNA, antisense RNA, alkylierenden Substanzen, Platinanaloga, interkalierenden Stoffen, Antibiotika, Mitosehemmern, Taxanen, Topoisomerase-Hemmern, Antimetaboliten, Hydroxycarbamid, Podophyllotoxin, Enzymen, Hormonen, Tumornekrosefaktor, Biomodulatoren ("biological response modifiers") und allen sonstigen bekannten zytotoxischen Stoffen.
  7. Das Poly(organo)phosphazenmolekülkonjugat nach einem der Ansprüche 1 bis 6, wobei das Polyalkylenoxid ausgewählt ist aus der Gruppe bestehend aus Polyether, Methoxypolyether, Ethoxypolyether, Polyethylenoxid, Polypropylenoxid, Polybutylenoxid, Polyethylenglycol, Polypropylenglycol, Polybutylenglycol, Methoxypolyethylenoxid, Methoxypolypropylenoxid, Methoxypolybutylenoxid, Methoxypolyethylenglycol, Methoxypolypropylenglycol, Methoxypolybutylenglycol, Ethoxypolyethylenoxid, Ethoxypolypropylenoxid, Ethoxypolybutylenoxid, Ethoxypolyethylenglycol, Ethoxypolypropylenglycol, Ethoxypolybutylenglycol, Poly(ethylenoxid-co-propylenoxid), Poly(ethylenglycol-co-propylenglycol), Poly(ethylenoxid-co-butylenoxid), Poly(ethylenglycol-co-butylenglycol), Poly(propylenoxid-co-butylenoxid), Poly(propylenglycol-co-butylenglycol), Methoxypoly(ethylenoxid-co-propylenoxid), Methoxypoly(ethylenglycol-co-propylenglycol), Methoxypoly(ethylenoxid-co-butylenoxid), Methoxypoly(ethylenglycol-co-butylenglycol), Methoxypoly(propylenoxid-co-butylenoxid), Methoxypoly(propylenglycol-co-butylenglycol), Ethoxypoly(ethylenoxid-co-propylenoxid), Ethoxypoly(ethylenglycol-co-propylenglycol), Ethoxypoly(ethylenoxid-co-butylenoxid), Ethoxypoly(ethylenglycol-co-butylenglycol), Ethoxypoly(propylenoxid-co-butylenoxid) und Ethoxypoly(propylenglycol-co-butylenglycol).
  8. Das Poly(organo)phosphazenmolekülkonjugat nach einem der Ansprüche 1 bis 7, wobei das Depsipeptid ein Peptid ist, in dem eine oder mehrere der Amid- (-CONHR-) Bindungen durch Ester- (COOR) Bindungen ersetzt sind.
  9. Das Poly(organo)phosphazenmolekülkonjugat nach einem der Ansprüche 1 bis 8, wobei das Depsipeptid ausgewählt ist aus der Gruppe bestehend aus Beativericin, Morpholindion, Valinomycin, Depsipeptid A, Depsipeptid B, Ethyl-2-(O-glycyl)glycolat und Ethyl-2-(O-glycyl)laktat.
  10. Das Poly(organo)phosphazenmolekülkonjugat nach einem der Ansprüche 1 bis 9, wobei der Aminosäurealkylester ein Ester einer Aminosäure und eines (C1 bis C10)-Alkanols ist.
  11. Das Poly(organo)phosphazenmolekülkonjugat nach einem der Ansprüche 1 bis 10, wobei der auf einen Tumor gerichtete Ligand ausgewählt ist aus der Gruppe bestehend aus Biotin, Folsäure, Vitamin B12, Riboflavin, Hyaluronsäure, monoklonalen Antikörpern gerichtet auf tumorspezifische Antigene und/oder tumorspezifische Rezeptoren und Varianten davon, mehrfach ungesättigten Fettsäuren, Aptameren gerichtet auf tumorspezifische Antigene und/oder tumorspezifische Rezeptoren, Oligopeptiden gerichtet auf tumorspezifische Antigene und/oder tumorspezifische Rezeptoren.
  12. Das Poly(organo)phosphazenmolekülkonjugat nach einem der Ansprüche 1 bis 11, wobei das Poly(organo)phosphazenmolekülkonjugat eine Polydispersität von 1.8 oder weniger aufweist.
  13. Verfahren zur Herstellung eines Poly(organo)phosphazenmolekülkonjugats nach einem der Ansprüche 1 bis 12, umfassend die Schritte:
    a) Herstellung von Dichloropolyphosphazen durch lebende kationische Polymerisation ("living cationic polymerisation") von Chlorophosphoranimen, wobei das polymerisierte Dichloropolyphosphazen aus Schritt a) vorzugsweise eine Polydispersität von 1.8 oder weniger aufweist;
    b) Substitution von mindestens einem Chloratom des Dichloropolyphosphazens aus Schritt a) mit einem pH-sensitiven Linker; und
    c) kovalentes Binden eines Antikrebsmittels an den pH-sensitiven Linker.
  14. Das Verfahren nach Anspruch 13, weiterhin umfassend den Schritt einer Substitution von mindestens einem Chloratom mit einem Polyalkylenoxid zwischen den Schritten b) und c), und/oder weiterhin umfassend den Schritt einer Substitution von mindestens einem Chloratom mit einem Depsipeptid zwischen den Schritten b) und c), und/oder weiterhin umfassend den Schritt einer Substitution von mindestens einem Chloratom mit einem Aminosäurealkylester zwischen den Schritten b) und c), und/oder weiterhin umfassend den Schritt einer Substitution von mindestens einem Chloratom mit einem auf einen Tumor gerichteten Liganden zwischen den Schritten b) und c).
  15. Poly(organo)phosphazenmolekülkonjugat erhältlich durch das Verfahren nach einem der Ansprüche 13 oder 14.
  16. Poly(organo)phosphazenkonjugat nach einem der Ansprüche 1 bis 12 oder Poly(organo)phosphazenmolekülkonjugat erhältlich durch das Verfahren nach einem der Ansprüche 13 or 14 zur Verwendung in der Medizin, insbesondere zur Verwendung bei der Behandlung von Krebs, vorzugsweise durch intravenöse Verabreichung.
  17. Pharmazeutische Zusammensetzung umfassend ein Polyorganophosphazen nach einem der Ansprüche 1 bis 12 oder ein Poly(organo)phosphazenmolekülkonjugat erhältlich durch das Verfahren nach einem der Ansprüche 13 or 14 und einen pharmazeutisch verträglichen Träger.
EP10752318.5A 2010-09-07 2010-09-07 Biologisch abbaubare wasserlösliche und ph-reaktive poly(organo)phosphazene Not-in-force EP2613810B9 (de)

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* Cited by examiner, † Cited by third party
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US10287321B2 (en) 2011-03-17 2019-05-14 The University Of Birmingham Re-directed immunotherapy

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KR102078806B1 (ko) 2014-03-14 2020-02-18 (주)씨앤팜 신규한 양이온성 폴리포스파젠 화합물, 폴리포스파젠-약물 컨쥬게이트 화합물 및 그 제조 방법
WO2015137777A1 (ko) * 2014-03-14 2015-09-17 (주)씨앤팜 신규한 양이온성 폴리포스파젠 화합물, 폴리포스파젠-약물 컨쥬게이트 화합물 및 그 제조 방법
KR20220101204A (ko) 2016-03-02 2022-07-19 에자이 알앤드디 매니지먼트 가부시키가이샤 에리불린-기반 항체-약물 콘주게이트 및 사용 방법
CN114983940B (zh) * 2022-06-28 2024-04-09 汉中职业技术学院 一种生物活性纳米胶束及其合成方法

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2653541B1 (fr) 1989-10-24 1995-02-10 Elf Aquitaine Dispositifs pour produire du froid et/ou de la chaleur par reaction solide-gaz geres par caloducs gravitationnels.
EP0425268A3 (en) * 1989-10-27 1992-03-25 Teijin Limited Phosphazene polymer carrier for biologically active substance
US5698664A (en) 1995-04-26 1997-12-16 The Penn State Research Foundation Synthesis of polyphosphazenes with controlled molecular weight and polydispersity
US5914388A (en) 1995-04-26 1999-06-22 The Penn State Research Foundation Synthesis polyphosphazenes with controlled molecular weight and polydisperity
KR100315630B1 (ko) 1999-11-17 2001-12-12 박호군 온도변화에 따라 상전이 거동을 갖는 분해성폴리포스파젠계 고분자 및 그 제조방법
KR100499340B1 (ko) 2003-04-29 2005-07-04 학교법인 이화학당 암 조직 선택성과 생분해성을 갖는폴리포스파젠-백금(ⅱ)착물 복합체 항암제 및 그 제조방법
KR100746962B1 (ko) 2006-04-04 2007-08-07 한국과학기술연구원 온도 감응성 포스파젠계 고분자-생리 활성 물질 복합체,그의 제조방법 및 그의 용도
KR100807358B1 (ko) 2007-04-18 2008-02-28 (주)나노하이브리드 암조직 선택성과 생분해성을 갖는 고리형 삼합체포스파젠-백금(ｉｉ) 착물 컨쥬게이트 항암제 및 그 제조방법

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10287321B2 (en) 2011-03-17 2019-05-14 The University Of Birmingham Re-directed immunotherapy

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